During the depressed phase of major depressive disorder and bipolar disorder, glucose metabolism is abnormally elevated in the amygdala, a brain structure that is critically involved in associating experiential stimuli with emotional significance and in organizing the endocrine, autonomic and behavioral responses to emotional stimuli. The magnitude of this elevation correlated positively with blood concentrations of the ?stress hormone?, cortisol. This relationship may reflect two phenomena that have been established in studies of rodents: the amygdala?s prominent role in mediating corticosterone (the rodent equivalent of cortisol) secretion during stressful conditions, and the direct enhancement of amygdala function by corticosterone. In response to viewing pictures of human faces showing sad expressions, the neural responses of the amygdala and the prefrontal cortex were abnormal in the depressed phase of both bipolar disorder and major depressive disorder. In both depressed and healthy control subjects the blood flow initially increased in the amygdala in response to sad faces. However, after repeatedly viewing the same sad faces, the amygdala stopped responding in the healthy subjects, but continued to respond in the depressed subjects. This abnormality was associated with abnormal responses of the prefrontal cortex to sad faces in the depressives, such that activity in the anterior cingulate and orbital cortex increased in healthy subjects, but decreased in depressed subjects. These latter regions are known to play important roles in regulating emotional responses generally, including those mediated by the amygdala.